title: Smooth muscle cell arachidonic acid release, migration, and proliferation are markedly attenuated in mice null for calcium-independent phospholipase A2beta.
abstract: Pharmacologic evidence suggests that the lipid products generated by one or more calcium-independent phospholipases A(2) (iPLA(2)s) participate in the regulation of vascular tone through smooth muscle cell (SMC) Ca(2+) signaling and the release of arachidonic acid. However, the recent identification of new members of the iPLA(2) family, each inhibitable by (E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one, has rendered definitive identification of the specific enzyme(s) mediating these processes difficult. Accordingly, we used iPLA(2)beta(-/-) mice to demonstrate that iPLA(2)beta is responsible for the majority of thapsigargin and ionophore (A23187)-induced arachidonic acid release from SMCs. Both thapsigargin and A23187 stimulated robust [(3)H]arachidonate (AA) release from wild-type aortic SMCs that was dramatically attenuated in iPLA(2)beta(-/-) mice (>80% reduction at 5 min; p < 0.01). Moreover, iPLA(2)beta(-/-) mice displayed defects in SMC Ca(2+) homeostasis and decreased SMC migration and proliferation in a model of vascular injury. Ca(2+)-store depletion resulted in the rapid entry of external Ca(2+) into wild-type aortic SMCs that was significantly slower in iPLA(2)beta-null cells (p < 0.01). Furthermore, SMCs from iPLA(2)beta-null mesenteric arterial explants demonstrated decreased proliferation and migration. The defects in migration and proliferation in iPLA(2)beta-null SMCs were restored by 2 mum AA. Remarkably, the cyclooxygenase-2-specific inhibitor, NS-398, prevented AA-induced rescue of SMC migration and proliferation in iPLA(2)beta(-/-) mice. Moreover, PGE(2) alone rescued proliferation and migration in iPLA(2)beta(-/-) mice. We conclude that iPLA(2)beta is an important mediator of AA release and prostaglandin E(2) production in SMCs, modulating vascular tone, cellular signaling, proliferation, and migration.
authors.affiliation: Division of Bioorganic Chemistry and Molecular Pharmacology, Endocrinology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Moon
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jenkins
authors.forename: David J
authors.initials: DJ
authors.lastname: Mancuso
authors.forename: John
authors.initials: J
authors.lastname: Turk
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009130:Muscle, Smooth; D009578:Nitrobenzenes / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007476:Ionophores; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D016718:Arachidonic Acid; D000001:Calcimycin; D054513:Group IV Phospholipases A2; D002118:Calcium